9UPU
Cryo-EM strucutre of CXCR4 complexed with agonist SDV1a
Summary for 9UPU
| Entry DOI | 10.2210/pdb9upu/pdb |
| EMDB information | 64402 |
| Descriptor | Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, Guanine nucleotide-binding protein G(i) subunit alpha-1, ... (7 entities in total) |
| Functional Keywords | cxc motif chemokine receptor 4, agonist, signaling protein, signaling protein-immune system complex, signaling protein/immune system |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 6 |
| Total formula weight | 192124.41 |
| Authors | |
| Primary citation | Sang, X.,Jiao, H.,Meng, Q.,Fang, X.,Sundaram, K.S.,Zhou, J.,Xu, Y.,Alvarado, A.I.W.,Nuryyev, R.L.,Ourenik, J.,Ourednik, V.,Huang, I.S.,Liu, X.,Mei, Y.,Qian, T.,Ciechanover, A.,Pizzo, D.P.,Lane, M.A.,Zholudeva, L.V.,An, J.,Snyder, E.Y.,Hu, H.,Huang, Z. The cryo-EM-delineated mechanism underlying mimicry of CXCR4 agonism enables widespread stem cell neuroprotection in a mouse model of ALS. Biorxiv, 2025 Cited by PubMed Abstract: G-protein coupled receptors (GPCRs) are transmembrane proteins that mediate a range of signaling functions and, therefore, offer targets for a number of therapeutic interventions. Chemokine receptor CXCR4, a GPCR, plays versatile roles in normal and abnormal physiological processes. Synthetic CXCR4 antagonists have been extensively studied and approved for the clinical treatment of cancer and other diseases. We recently elucidated the structural mechanisms underlying CXCR4 antagonism using cryogenic electron microscopy (cryo-EM). CXCR4 agonism by synthetic molecules is an unanticipated therapeutic intervention we recently unveiled. The structural mechanisms underlying those actions remain poorly understood yet could help elucidate a new class of drugs. Here we demonstrate a synthetic dual-moiety strategy that combines simplified agonistic and antagonistic moieties taken from natural agonistic and antagonistic chemokines, respectively, to design de novo peptide mimics of biological function of natural CXCR4 agonist SDF-1α. Two peptides so generated, SDV1a and SDVX1 were shown to mimic the action of SDF-1α in activating CXCR4 signaling pathways and cell migration. The structural mechanism of these peptides in the mimicry of CXCR4 agonism was illustrated by cryo-EM structures of CXCR4 bound and activated by the peptides in the presence of G protein, revealing common interactions with the receptor by these peptides in comparison with SDF-1α that explain their close mimicry and conformational changes leading to CXCR4 signal activation. The therapeutic benefit of one of these peptides, SDV1a, was demonstrated in the SOD1 mouse model of the spinal motor neuron degenerative disease, amyotrophic lateral sclerosis (ALS) wherein the success of neuroprotective actions of transplanted human neural stem cells (hNSCs) is directly correlated with the expanse of diseased neuroaxis traversed by the donor cells; SDV1a enabled broader neuroprotective coverage while also permitting a much less invasive route of cell administration for extending life. Taken together, these results provide insights into the structural determinants of therapeutic CXCR4 agonism which may allow the design of adjunctive drugs that improve cell-based treatments of central nervous system (CNS) diseases. PubMed: 40672153DOI: 10.1101/2025.07.08.663251 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.8 Å) |
Structure validation
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